{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n AKR1B10, a member of the aldo‐keto reductase superfamily, plays a multifaceted role in cancer biology by integrating metabolic reprogramming with cellular detoxification and proliferative signaling. It functions as an efficient retinaldehyde reductase that converts retinaldehyde into retinol, thereby down‐regulating retinoic acid synthesis and promoting cell proliferation in various tumors—including hepatocellular, lung, and colorectal cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, AKR1B10 is highly effective in detoxifying reactive carbonyl species (such as lipid‑peroxidation–derived aldehydes and dietary unsaturated carbonyls), which not only protects cells from cytotoxic stress but also contributes to pro‐oncogenic processes by influencing isoprenoid homeostasis and steroid metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, AKR1B10 has been implicated in the regulation of lipid synthesis. In tumorigenic mammary epithelial cells, for example, it associates with and stabilizes acetyl‐CoA carboxylase, thereby enhancing de novo fatty acid synthesis—a critical process that supports the rapid growth of cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Its overexpression also contributes to chemoresistance and metastatic behavior; elevated levels have been linked to enhanced survival, increased invasive capabilities (including the facilitation of blood–brain barrier extravasation in lung cancer), and modulation of matrix metalloproteinases via the MEK/ERK pathway."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n The expression of AKR1B10 is regulated by stress‐responsive transcription factors. Activation of the NRF2 pathway by oxidative/electrophilic stress (or via fumarate accumulation in fumarate hydratase–deficient tumors) as well as mitogenic signals mediated by factors like EGF and insulin (through AP‑1) up‑regulate AKR1B10 expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": " Such regulatory inputs help cancer cells counteract cytotoxic insults while simultaneously enhancing metabolic pathways that support tumor growth. In some tumor types, AKR1B10 may also be directly influenced by p53 signaling, linking its expression to apoptotic responses and tumor suppression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Clinically, the overexpression of AKR1B10 has been observed in early-stage tumors and is associated with altered lipogenesis, enhanced detoxification, chemotherapy resistance, and, in some cases, favorable prognostic features. Its presence in body fluids—owing to a nonclassical lysosome-mediated secretory pathway—further underscores its potential as a non-invasive biomarker for cancer diagnosis and monitoring."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In addition, oncogenic signaling axes involving AKR1B10 (for instance, through interactions with microRNAs and ERK signaling in lung adenocarcinoma) as well as its role in modulating protein prenylation in pancreatic cancer, highlight its promise as a therapeutic target across multiple cancer types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, comparative structural and enzymatic studies have revealed that AKR1B10 exhibits substrate specificity and catalytic efficiency superior to that of closely related family members (such as AKR1B1), which offers opportunities for the design of selective inhibitors that may be utilized in cancer intervention strategies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Overall, the multifaceted functions of AKR1B10—involving detoxification, metabolic regulation, and signal transduction—cement its role as a pivotal enzyme in carcinogenesis and establish it as a promising diagnostic, prognostic, and therapeutic target in oncology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Oriol Gallego, F Xavier Ruiz, Albert Ardèvol, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0705659105"}], "href": "https://doi.org/10.1073/pnas.0705659105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18087047"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18087047"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Tomoko Ohashi, Masashi Idogawa, Yasushi Sasaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-13-0330-T"}], "href": "https://doi.org/10.1158/1541-7786.MCR-13-0330-T"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24140838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24140838"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Satoshi Endo, Toshiyuki Matsunaga, Hiroaki Mamiya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinetic studies of AKR1B10, human aldose reductase-like protein: endogenous substrates and inhibition by steroids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2009.05.009"}], "href": "https://doi.org/10.1016/j.abb.2009.05.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19464995"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19464995"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yi Shen, Linlin Zhong, Stephen Johnson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human aldo-keto reductases 1B1 and 1B10: a comparative study on their enzyme activity toward electrophilic carbonyl compounds."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chem Biol Interact (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cbi.2011.02.004"}], "href": "https://doi.org/10.1016/j.cbi.2011.02.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21329684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21329684"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Toru Nishinaka, Takeshi Miura, Manami Okumura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of aldo-keto reductase AKR1B10 gene expression: involvement of transcription factor Nrf2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chem Biol Interact (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cbi.2011.01.026"}], "href": "https://doi.org/10.1016/j.cbi.2011.01.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21277289"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21277289"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jun Ma, Ruilan Yan, Xuyu Zu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M707650200"}], "href": "https://doi.org/10.1074/jbc.M707650200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18056116"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18056116"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Andreas Bitter, Petra Rümmele, Kathrin Klein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Toxicol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00204-014-1348-x"}], "href": "https://doi.org/10.1007/s00204-014-1348-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25182422"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25182422"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ruilan Yan, Xuyu Zu, Jun Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldo-keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: Implication for cancer intervention."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.22933"}], "href": "https://doi.org/10.1002/ijc.22933"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17597105"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17597105"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Wenwen Liu, Jing Song, Xiaohui Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AKR1B10 (Aldo-keto reductase family 1 B10) promotes brain metastasis of lung cancer cells in a multi-organ microfluidic chip model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biomater (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.actbio.2019.04.053"}], "href": "https://doi.org/10.1016/j.actbio.2019.04.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31034948"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31034948"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kristina A Matkowskyj, Han Bai, Jie Liao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldoketoreductase family 1B10 (AKR1B10) as a biomarker to distinguish hepatocellular carcinoma from benign liver lesions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Pathol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.humpath.2013.12.002"}], "href": "https://doi.org/10.1016/j.humpath.2013.12.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24656094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24656094"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Aikseng Ooi, Jing-Chii Wong, David Petillo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.08.024"}], "href": "https://doi.org/10.1016/j.ccr.2011.08.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22014576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22014576"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "A Kenneth MacLeod, Michael McMahon, Simon M Plummer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgp176"}], "href": "https://doi.org/10.1093/carcin/bgp176"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19608619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19608619"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Akhileshwar Namani, Md Matiur Rahaman, Ming Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene-expression signature regulated by the KEAP1-NRF2-CUL3 axis is associated with a poor prognosis in head and neck squamous cell cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12885-017-3907-z"}], "href": "https://doi.org/10.1186/s12885-017-3907-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29306329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29306329"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ziwen Liu, Ruilan Yan, Ahmed Al-Salman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20111322"}], "href": "https://doi.org/10.1042/BJ20111322"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22329800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22329800"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Di-xian Luo, Mei C Huang, Jun Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldo-keto reductase family 1, member B10 is secreted through a lysosome-mediated non-classical pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20110111"}], "href": "https://doi.org/10.1042/BJ20110111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21585341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21585341"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Zhuangzhuang Cong, Yifei Diao, Yang Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long non-coding RNA linc00665 promotes lung adenocarcinoma progression and functions as ceRNA to regulate AKR1B10-ERK signaling by sponging miR-98."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-1361-3"}], "href": "https://doi.org/10.1038/s41419-019-1361-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30692511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30692511"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yeon Tae Chung, Kristina A Matkowskyj, Haonan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mod Pathol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/modpathol.2011.191"}], "href": "https://doi.org/10.1038/modpathol.2011.191"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22222635"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22222635"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Liping Zhang, Hong Zhang, Yining Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibitor selectivity between aldo-keto reductase superfamily members AKR1B10 and AKR1B1: role of Trp112 (Trp111)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2013.09.031"}], "href": "https://doi.org/10.1016/j.febslet.2013.09.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24100137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24100137"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Hyuk-Joon Lee, Ki Taek Nam, Heae Surng Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene expression profiling of metaplastic lineages identifies CDH17 as a prognostic marker in early stage gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2010.04.008"}], "href": "https://doi.org/10.1053/j.gastro.2010.04.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20398667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20398667"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "H Yoshitake, M Takahashi, H Ishikawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldo-keto reductase family 1, member B10 in uterine carcinomas: a potential risk factor of recurrence after surgical therapy in cervical cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Gynecol Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1525-1438.2007.00932.x"}], "href": "https://doi.org/10.1111/j.1525-1438.2007.00932.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17425679"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17425679"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Stefan Heringlake, Michael Hofdmann, Anette Fiebeler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and expression analysis of the aldo-ketoreductase1-B10 gene in primary malignant liver tumours."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hepatol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jhep.2009.11.005"}], "href": "https://doi.org/10.1016/j.jhep.2009.11.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20036025"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20036025"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Klaus J Schmitz, Georgios C Sotiropoulos, Hideo A Baba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Liver Int (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1478-3231.2011.02511.x"}], "href": "https://doi.org/10.1111/j.1478-3231.2011.02511.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21645211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21645211"}]}]}]}